Stroke is a major cause of death throughout the world and its prevalence is increasing with increased longevity and obesity-associated vascular disease. There are, however, very few effective therapeutics. During the last few years we have identified a broadly neuroprotective lead compound for stroke and have synthesized a series of derivatives that fall into two classes. One group has BDNF-like activity and is active in cell culture assays for glucose starvation, oxidative stress, and trophic factor withdrawal. The best lead has an EC50 in some of these assays below 10 nanomolar. The other group inhibits glutamate-induced excitotoxicity, but needs to be improved via combinatorial and medicinal chemistry to lower its EC50. Both groups of compounds are active in cell culture models of in vitro ischemia. One of our initial leads enhances memory in rodents and is neuroprotective in a rabbit ischemia model. It is the goal of this proposal to synthesize and improve the pharmacological properties of both classes of drugs through synthetic chemistry and to identify their specific targets and molecular pathways that lead to neuroprotection. This information will not only help us improve our drugs but also open the possibility of identifying new targets for drug development. Finally, these compounds will be put into a rigorous rabbit ischemia model both individually and in combination to determine their potential for clinical development. We feel that at the end of this work we will have identified a completely new class of neuroprotective compounds, understand how they function, and demonstrated the feasibility for their pre-clinical development for stroke.